The work, as detailed in this proposal, has focused on the mechanism(s) of protection that Suppressor of Cytokine Signaling - 1 (SOCS-1) confers in the setting of hyperoxic acute lung injury (HALI). Our preliminary data demonstrated that adenoviral treated mice that overexpress the suppressor of cytokine signaling-1(Ad-SOCS-1) are remarkably resistant to hyperoxic acute lung injury (HALI) and live significantly longer in hyperoxia when compared to green fluorescent protein tagged adeno virus (Ad-GFP) treated mice. SOCS-1 overexpressing mice are protected from hyperoxia-induced inflammation, which is associated with inactivation of purinergic P2X7 receptor (P2X7R)-mediated inflammasome, thus demonstrating a critical role for SOCS-1 in inflammasome-mediated inflammation. Either inflammasome silencing or SOCS-1 overexpression in monocytic cell line (THP-1) and co-cultured with alveolar type II (ATII) monolayer abolishes hyperoxia induced transepithelial permeability across mouse ATII cell monolayers and abrogates hyperoxia-induced secretion of pro-inflammatory cytokines. SOCS-1 overexpressing mice are protected from hyperoxia-induced inflammation and apoptosis, which is associated with apoptosis signal-regulating kinase 1 (ASK-1) inhibition. SOCS-1- induced protection against oxidant-induced death-inducing signaling complex (DISC) mediated apoptosis is associated with ASK-1 ubiquitination and degradation. These studies lead us to hypothesize that SOCS-1 confers protection against HALI by inhibiting inflammasome-mediated inflammation and DISC-induced apoptosis via ASK-1 degradation. We propose the following specific aims to investigate our hypothesis: Aim 1: To identify the role of ASK-1 in SOCS-1-induced protection against hyperoxia-induced DISC and inflammasome formation. Aim 2: To determine whether activation of ASK-1 has a role in hyperoxia-induced P2X7R mediated inflammasome formation. Aim 3: To identify the role of inflammasome in SOCS-1-induced protection against hyperoxia-induced inflammation and epithelial permeability. The proposed studies will elucidate the mechanisms by which SOCS-1 protects against HALI and will identify the cellular processes and genes critical for protection of the lung. The proposed studies will elucidate the precise role of SOCS-1 mediated inflammasome in acute lung injury (ALI) could also lead to the discovery of a totally novel therapeutic class of drugs that suppresses inflammation in ALI.